Clopidogrel In Acute Coronary Syndrome Patients Research Articles

Comparative Efficacy and Safety of Novel Antiplatelets and Standard Therapy in Patients With Coronary Artery Disease.

Coronary artery disease (CAD) is a significant health concern that has affected approximately 110 million people worldwide. CAD is defined as persistent narrowing of the coronary arteries as a result of atherosclerotic plaque build-up. Acute coronary syndrome (ACS), which encompasses ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), and unstable angina, often results from plaque ruptures. Platelets are crucial for atherogenesis, vascular inflammation, and oxidative stress. Antiplatelet therapy aimed at reducing thrombotic events is vital for ACS treatment. Clinical guidelines advise the use of dual antiplatelet therapy (DAPT) that combines aspirin and a P2Y12 receptor inhibitor (clopidogrel, prasugrel, or ticagrelor) in ACS patients undergoing percutaneous intervention (PCI). This study aimed to assess comprehensively the effectiveness and safety of ticagrelor and prasugrel in comparison to clopidogrel in patients with ACS. An extensive literature search was conducted using PubMed, PubMed Central (PMC), ScienceDirect, and EBSCO databases. The search revealed studies that compared ticagrelor and prasugrel to clopidogrel in ACS patients, and we selected these studies based on specific inclusion and exclusion criteria, which included observational studies, clinical trials, literature reviews, and meta-analyses involving adult ACS patients treated with ticagrelor, prasugrel, or clopidogrel. The efficacy outcomes were defined as major adverse cardiovascular events (MACE) and thrombotic events, whereas the safety outcomes were measured by major and minor bleeding and hemorrhagic stroke. After a rigorous quality assessment to minimize bias, 23 studies were selected for analysis. The findings indicated that novel antiplatelets reduced MACE but increased bleeding complications, with ticagrelor consistently associated with dyspnea.In conclusion, novel P2Y12 inhibitors provide cardiovascular benefits but require careful patient selection and monitoring due to gastrointestinal bleeding (GIB) risks. Future research should standardize bleeding definitions and assess long-term outcomes. Ticagrelor and prasugrel may be more effective and safer than clopidogrel in ACS patients. Given the high risk of GIB, especially among older individuals or those with a past stroke, it is advisable to suggest a lower prasugrel dose without raising the bleeding rates. Since fewer patients use the novel antiplatelet regimen compared to clopidogrel, future clinical trials should include a broader patient population and compare these regimens.

761 PRASUGREL OR CLOPIDOGREL IN PATIENTS WITH ACUTE CORONARY SYNDROMES AT DIFFERENT THROMBOTIC RISK: RESULTS FROM THE PROMETHEUS STUDY

Abstract Background Potent P2Y12 inhibitors are recommended in patients with acute coronary syndrome (ACS), although the optimal antithrombotic strategy should be tailored based on patients thrombotic and hemorrhagic risk profile. We evaluated if the benefits associated with prasugrel vs. clopidogrel in ACS patients undergoing percutaneous coronary intervention (PCI) are similar in patients with different thrombotic risk profiles. Methods PROMETHEUS was a multicenter observational study comparing prasugrel vs. clopidogrel in ACS patients undergoing PCI. Patients were defined at high thrombotic risk if presenting with a clinical and a procedural risk feature. The primary endpoint was major adverse cardiac events (MACE), composite of death, myocardial infarction, stroke, or unplanned revascularization. Hazard ratio (HR) and 95% confidence intervals (CI) were calculated using propensity-stratified analysis and with multivariable Cox regression. Results Among 16,065 patients, 4,293 were defined at high and 11,772 at low-to-moderate thrombotic risk. Patients receiving prasugrel had less comorbidities and risk factors than those treated with clopidogrel, both in the high and low-to-moderate thrombotic risk strata. High thrombotic risk patients had increased rates of ischemic and bleeding events at 90-day and 1-year follow-up. Patients treated with prasugrel had a lower adjusted 1-year risk of MACE (HR 0.86, 95% CI 0.77-0.96), irrespective of their thrombotic risk (pinteraction =0.32). Stratifying the study population by number of risk factors there was a significant interaction (pinteraction =0.026) for a greater reduction in MACE with prasugrel among patients with ≤1 thrombotic risk factor. The risk of clinically significant bleeding was similar in patients treated with prasugrel and clopidogrel. Conclusions Patients with ACS at high thrombotic risk who undergo PCI are at increased risk of adverse events at 1 year. Prasugrel, mainly reserved to patients with less comorbidities, reduced the risk of ischemic events both in patients at high and low-to-moderate thrombotic risk as compared with clopidogrel.

Comparison between ticagrelor and clopidogrel in high bleeding risk patients with acute coronary syndrome

Abstract Background Potent antiplatelet agents such as ticagrelor are associated with a lower risk of ischemic events than clopidogrel in patients with acute coronary syndrome (ACS). However, it is uncertain whether the benefits of more intensive anti-ischemic therapy outweigh the risks of major bleeding in individuals who have a high bleeding risk (HBR). This study aimed to assess treatment outcomes following dual antiplatelet therapy (DAPT) using either ticagrelor or clopidogrel in ACS patients with HBR. Methods All HBR patients enrolled in the SWEDEHEART registry who were discharged with DAPT using ticagrelor or clopidogrel following ACS between 2010 and 2017 were included in this study. Bleeding risk was assessed using the 4-item PRECISE-DAPT score, which consists of age, prior bleeding, haemoglobin concentration and creatinine clearance. HBR was defined as a PRECISE-DAPT score ≥25. Inverse-probability of treatment weighting was used to adjust for baseline differences between the treatment groups. The main analysis consisted of a doubly robust estimation of causal effect using Cox proportional hazards models. Data on major bleeding, recurrent myocardial infarction (MI), ischemic stroke and all-cause mortality was obtained from national registries, with 365 days of follow-up. Additional outcomes include major adverse cardiovascular events (MACE), a composite of MI, ischemic stroke and all-cause mortality, and net adverse clinical events (NACE), a composite of MACE and major bleeding. Results Of all ACS patients, 36% (n=25,042) had a PRECISE-DAPT score ≥25. Approximately half of the study participants were treated with ticagrelor (n=11,848). Ticagrelor reduced the risk of MI (hazard ratio [HR], 0.82 [95% CI 0.74–0.91]), ischemic stroke (HR, 0.73 [95% CI 0.60–0.88]) and MACE (HR, 0.90 [95% CI 0.84–0.97]), while also increasing the risk of major bleeding compared to clopidogrel (HR, 1.30 [95% CI 1.16–1.47]). We found no significant differences in all-cause mortality (HR 1.02 [95% CI 0.92–1.12]) and NACE (HR 0.98 [95% CI 0.92–1.05]). Conclusions Ticagrelor was associated with a lower risk of recurrent ischemic events, but a higher risk of major bleeding compared to clopidogrel. There were no significant differences in all-cause mortality and NACE between the treatment groups. These results suggest that more potent antiplatelet agents might not be superior to clopidogrel in ACS patients with HBR. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Stockholm county council

In-hospital outcomes of Ticagrelor versus Clopidogrel in high bleeding risk patients with acute coronary syndrome: Findings from the CCC-ACS project

BackgroundThe optimal P2Y12 inhibitor in high bleeding risk (HBR) patients with acute coronary syndrome (ACS) remains unclear. We compared the in-hospital efficacy and safety of ticagrelor versus clopidogrel in ACS patients at HBR. MethodsWe identified 22,120 hospitalized ACS patients with HBR treated with aspirin combined with either clopidogrel (n = 17,420) or ticagrelor (n = 4700) in the Improving Care for Cardiovascular Disease in China-ACS (CCC-ACS) project between November 2014 and December 2019. ResultsThe median length of hospital stay was 10 days (interquartile range, 7–14 days). Compared with clopidogrel, ticagrelor was associated with a higher risk of in-hospital TIMI major or minor bleeding (4.8% vs 3.8%; adjusted OR 1.20; 95% CI 1.03–1.41; P = 0.022). The incidence of TIMI major bleeding (1.7% vs 1.1%, P = 0.005) and intracranial bleeding (0.8% vs 0.5%, P = 0.005) were also higher in the ticagrelor group than in the clopidogrel group. There was no significant difference in the rate of in-hospital major adverse cardiovascular and cerebrovascular event (MACCE) (a composite of all-cause death, myocardial infarction, stent thrombosis, or ischemic stroke) with ticagrelor compared with clopidogrel therapy (4.2% vs 4.3%; adjusted OR 1.08; 95% CI 0.90–1.28; P = 0.411). Outcomes in the propensity-matched cohorts and in sensitivity analyses were consistent with the those of the main analysis. ConclusionsAmong ACS patients with HBR, ticagrelor as compared with clopidogrel was associated with an increased risk of in-hospital major bleeding without a significant reduction in in-hospital MACCE. Clinical trial registrationhttps://www.clinicaltrials.gov. Unique identifier: NCT02306616.

Ticagrelor versus clopidogrel in patients with acute coronary syndrome undergoing complex percutaneous coronary intervention.

To evaluate the effectiveness and safety of ticagrelor versus clopidogrel in patients with acute coronary syndromes (ACS) undergoing complex percutaneous coronary intervention (PCI). It remains inconclusive whether ticagrelor is superior to clopidogrel in ACS patients undergoing complex PCI in real-world practice. Based on an all-comers PCI registry, we compared the long-term effectiveness and safety between ticagrelor and clopidogrel in ACS patients undergoing complex PCI, defined as PCI procedures for complex lesions including bifurcation, chronic total occlusion, ostial, tortuous, calcific, diffused, thrombus-containing, and restenotic lesions. The primary ischemic outcome was a composite of cardiac death, myocardial infarction, or stroke. The safety outcome comprised Bleeding Academic Research Consortium (BARC) types 2, 3, and 5 bleeding. Propensity score matching (PSM) was performed to reduce bias. Among ACS patients who underwent complex PCI, 4373 (35.2%) and 8065 (64.8%) received dual antiplatelet therapy based on ticagrelor and clopidogrel, respectively. The incidences of composite ischemic events (before PSM: 1.74% vs. 2.84%; after PSM: 1.50% vs. 2.65%; p < 0.01 for both) and all-cause death (before PSM: 1.23% vs. 2.12%, p < 0.01; after PSM: 1.09% vs. 1.81%, p = 0.02) were significantly lower in the ticagrelor-treated than in the clopidogrel-treated group. There was no significant difference in BARC types 2, 3, and 5 bleeding between groups. Whilst the risk of major bleeding was comparable between the two drugs, ticagrelor was associated with a significantly lower risk of ischemic events than clopidogrel in ACS patients undergoing complex PCI.

Abstract 13919: Ticagrelor versus Clopidogrel in Patients With Acute Coronary Syndrome: A Meta-Analysis

Introduction: P2Y 12 receptor antagonists are potent antiplatelet medications used in acute coronary syndrome (ACS). As compared to clopidogrel, ticagrelor has been shown to decrease the risk of myocardial infarction, stroke, and mortality. However, ticagrelor’s effect on the microcirculation of the coronary arteries is not well defined. Methods/Results: This meta-analysis compares the index of microcirculatory resistance (IMR), coronary flow reserve (CFR), and fractional flow reserve (FFR) of ticagrelor versus clopidogrel in ACS patients immediately post-PCI. Four randomized controlled trials were included with 375 patients. IMR was significantly lower in the ticagrelor arm (mean difference (MD) -6.34, 95% confidence interval (CI) -8.60 to -4.09, p&lt;0.00001, I 2 =66%) (Figure 1). CFR was significantly higher in the ticagrelor arm (MD 0.26, 95% CI 0.04-0.47, p=0.02, I 2 =0%). Finally, FFR was determined to be similar between ticagrelor and clopidogrel. Conclusion: This meta-analysis shows that ticagrelor significantly decreases IMR and subsequently the risk of myocardial damage and microvascular injury. Ticagrelor is also associated with significantly higher values of CRF and thus a decreased plaque burden and microvascular burden. In correlation with the decreased adverse effects, ticagrelor may be more efficacious in improving microcirculation than clopidogrel immediately post-PCI in patients who present with ACS.

Prasugrel or clopidogrel in patients with acute coronary syndromes at high thrombotic risk: results from the PROMETHEUS study

Abstract Background Potent P2Y12 inhibitors are recommended on top of aspirin in patients presenting with acute coronary syndrome (ACS). However, guideline recommendations suggest that the optimal antithrombotic strategy should be tailored based on patients thrombotic and hemorrhagic risk profile. Purpose It is poorly investigated if the benefits derived from potent P2Y12 inhibition in patients with ACS depend on the individual thrombotic risk profile. Our aim was to evaluate if the benefits associated with prasugrel vs. clopidogrel in patients with ACS undergoing percutaneous coronary intervention (PCI) are similar in case of different thrombotic risk profiles. Methods PROMETHEUS was a multicenter observational study comparing prasugrel vs. clopidogrel in ACS patients undergoing PCI. According to the 2020 ESC guidelines for non-ST elevation-ACS, patients are defined at high thrombotic risk if presenting with a clinical (diabetes mellitus requiring medication, history of recurrent myocardial infarction [MI], multivessel coronary artery disease [CAD], polyvascular [coronary and peripheral] disease, premature (&amp;lt;45 years) CAD, and chronic kidney disease [estimated glomerular filtration rate &amp;lt;60 ml/min/1.73m2]) and procedural (≥3 stents implanted, ≥3 lesions treated, total stent length &amp;gt;60 mm, complex revascularization [left main PCI, bifurcation or chronic total occlusion]) risk features. The primary endpoint was major adverse cardiac events (MACE), a composite of death, MI, stroke or unplanned revascularization. Hazard ratio (HR) and 95% confidence intervals (CI) were calculated using propensity-stratified analysis to assess the effect of prasugrel vs. clopidogrel and with multivariable Cox regression to evaluate the impact of thrombotic risk. Results Among 16065 patients, 4293 were defined at high thrombotic risk and 11772 at low-to-moderate thrombotic risk. Patients treated with prasugrel had less comorbidities and risk factors than those treated with clopidogrel, both in the high and low-to-moderate thrombotic risk strata. Patients at high thrombotic risk had higher rates of both ischemic and bleeding events at 90 days and at 1 year. Patients treated with prasugrel had a lower adjusted risk of MACE at 1 year (HR 0.86, 95% CI 0.77–0.96), with no significant interaction between effect estimates and thrombotic risk. However, after stratifying the study population by the number of risk factors, there was a significant interaction for a greater reduction in MACE with prasugrel in patients with ≤1 thrombotic risk factor. Conversely, there were no differences in major bleeding among patients treated with prasugrel and clopidogrel. Conclusions Patients with ACS at high thrombotic risk who undergo PCI are at increased risk of adverse events. Prasugrel, although mainly reserved to patients with lower burden of comorbidities, reduced the risk of ischemic events both in patients at high and low-to-moderate thrombotic risk as compared with clopidogrel. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo and Eli Lilly and Company Clinical outcomes at 1 year.Impact of number of risk factors

Cost-Effectiveness of Ticagrelor Compared with Clopidogrel in Patients with Acute Coronary Syndrome from Vietnamese Healthcare Payers' Perspective.

The PLATelet inhibition and patient Outcomes (PLATO) trial (NCT00391872) demonstrated that ticagrelor compared to clopidogrel significantly reduced the rate of death from cardiovascular causes, myocardial infarction or stroke in patients with acute coronary syndrome (ACS). The aim of this study is to analyze the long-term cost-effectiveness of ticagrelor compared to clopidogrel in ACS patients from a Vietnamese healthcare payers' perspective. A two-part cost-effectiveness model was developed to estimate long-term costs and quality-adjusted life-years (QALY). Cardiovascular event rates, hospital bed days, interventions, investigations, study drug utilization and EuroQol 5 Dimension (EQ-5D) data were derived from the PLATO trial. Unit costs of medical services were derived from the Vietnamese governmental price list, and drug costs were based on the weighted average price from the Vietnamese social security report (in VND; 10.000 VND = 0.405 USD). An annual discount rate of 3% was used. Probabilistic and deterministic sensitivity analyses were conducted to evaluate uncertainty of the results. Ticagrelor was associated with an incremental cost of VND 5.34 million (USD 216.49) and a QALY gain of 0.11. This resulted in a cost per QALY gained of VND 49.58 million (USD 2009.96) from the Vietnamese healthcare payers' perspective. Probabilistic sensitivity analysis indicates that ticagrelor has 59% probability of being cost-effective compared with clopidogrel when using a willingness-to-pay threshold of one gross domestic products (GDP) per capita. Deterministic sensitivity analysis using clinical outcomes from the Asian sub-population of PLATO resulted in a cost per QALY of VND 42.25 million (USD 1712.80). Ticagrelor can be considered a cost-effective treatment for ACS compared with clopidogrel from a Vietnamese healthcare payers' perspective.

High glycated albumin is an independent predictor of low response to clopidogrel in ACS patients: a cross-sectional study

BackgroundGlycated albumin (GA) is a marker of short-term glycemic control and is strongly associated with the occurrence of diabetes. Previous studies have shown an association between GA and the effect of clopidogrel therapy on ischemic stroke. However, limited information is available regarding this relationship in acute coronary syndrome (ACS) patients. In this study, we evaluated the effect of GA on platelet P2Y12 inhibition by clopidogrel in patients with ACS.MethodsConsecutive Chinese patients with ACS who received loading or maintenance doses of clopidogrel in addition to aspirin were recruited. At least 12 h after the patient had taken the clopidogrel dose, thromboelastography (TEG) and light transmittance aggregometry (LTA) were used to calculate the quantitative platelet inhibition rate to determine clopidogrel-induced antiplatelet reactivity. A prespecified cutoff of the maximum amplitude of adenosine diphosphate (ADP)-induced platelet-fibrin clot strength > 47 mm plus an ADP-induced platelet inhibition rate < 50% assessed by TEG or ADP-induced platelet aggregation > 40% assessed by LTA to indicate low responsiveness to clopidogrel were applied for evaluation. Patients were categorized into two groups based on a GA level of 15.5%, the cutoff point indicating the development of early-phase diabetes. Multivariate linear regression analysis was used to assess the interaction of GA with clopidogrel antiplatelet therapy.ResultsA total of 1021 participants were evaluated, and 28.3% of patients (289 of 1021) had low responsiveness to clopidogrel assessed by TEG. In patients with elevated GA levels, low responsiveness to clopidogrel assessed by TEG was observed in 33.7% (139 of 412) of patients, which was a significantly higher rate than that in the lower-GA-level group (24.6%, P = 0.002). According to multivariate linear regression analysis, a GA level > 15.5% was independently associated with low responsiveness to clopidogrel after adjustment for age, sex and other conventional confounding factors. This interaction was not mediated by a history of diabetes mellitus. A GA level ≤ 15.5% was associated with a high positive value [75.4%, 95% CI 73.0–77.6%] for predicting a normal responsiveness to clopidogrel.ConclusionsGA could be a potential biomarker to predict the effects of clopidogrel antiplatelet therapy in ACS patients and might be a clinical biomarker to guide DAPT de-escalation.

MicroRNA-605 rs2043556 polymorphisms affect clopidogrel therapy through modulation of CYP2B6 and P2RY12 in acute coronary syndrome patients

Clopidogrel therapy reduces the occurrence of major vascular events in acute coronary syndrome (ACS) patients, but treatment efficacy is variable. The present study aims to determine the mechanisms that underlie associations between certain miRNA polymorphisms and clinical outcomes of clopidogrel therapy. Our study focused on 9 miRNA single nucleotide polymorphisms in addition to CYP2C19*2 and CYP2C19*3. We found that the miR-605 rs2043556 AG genotype significantly decreased the risk of acute myocardial infarction (odds ratio, OR = 0.13, 95%CI 0.02–0.96, P = .045) and that the rs2043556 GG genotype significantly decreased the risk of unstable angina (OR = 0.19, 95%CI 0.05–0.65, P = .008) in ACS patients receiving clopidogrel therapy for more than one year. Dual-luciferase analysis indicated that miR-605 significantly decreased the mRNA expression of CYP2B6 and P2RY12 (P < .01). In cells treated with miR-605-A, the protein and mRNA expression of CYP2B6 and P2RY12 were significantly lower than that of cells treated with miR-605-G (P < .05). The results demonstrate that miR-605 targets the mRNA of the CYP2B6 and P2RY12 genes, and that rs2043556 A/G polymorphisms in miR-605 modulate the mRNA and protein expression of CYP2B6 and P2RY12 differently, which may impact the effect of clopidogrel in ACS patients.

Half-dose ticagrelor versus high-dose clopidogrel in reducing platelet reactivity in acute coronary syndrome patients with high on-clopidogrel platelet reactivity (divide study).

High on-treatment platelet reactivity (HTPR) after clopidogrel administration in patients with acute coronary syndrome (ACS) has been associated with an increased risk of adverse events. Our previous studies reported that half-dose ticagrelor provides a similar inhibitory effect on adenosine diphosphate (ADP)-induced platelet aggregation as standard-dose ticagrelor, but half-dose of ticagrelor has not been studied in Chinese ACS patients with HTPR. This study aimed to compare the antiplatelet action of half-dose ticagrelor with high-dose clopidogrel in ACS patients with HTPR. In this single-center randomized controlled trial, 80 (of 418 screened, 19.13%) ACS patients with HTPR while on clopidogrel were randomized to either half-dose ticagrelor (90mg LD, then 45mg twice daily) or high-dose clopidogrel (150mg once daily). Platelet function was assessed by thromboelastography (TEG) and light transmission aggregometry (LTA), and adverse events were monitored throughout the study for 30days. The ADP-induced platelet inhibition rate (IR) as measured by TEG was significantly higher for half-dose ticagrelor compared with high-dose clopidogrel (70.40% [61.10%-91.70%] vs. 44.25% [34.67%-79.07%], p = 0.001). The repeated HTPR rate was dramatically higher for high-dose clopidogrel compared with half-dose ticagrelor (6 of 32, 18.75% vs. 1 of 35, 2.85%; p = 0.04). No patients in either treatment group exhibited a major bleeding event or other adverse events. In ACS patients with HTPR, half-dose ticagrelor is more effective than high-dose clopidogrel in reducing platelet reactivity (NCT03062462).

High and low on-treatment platelet reactivity to P2Y12 inhibitors in a contemporary cohort of acute coronary syndrome patients undergoing percutaneous coronary intervention

IntroductionThere is compelling evidence supporting the association between high on-treatment platelet reactivity (HPR) and low on-treatment platelet reactivity (LPR) to clopidogrel with atherothrombotic and bleeding events, respectively. However, it is uncertain if current cutoff values should be used in prasugrel- or ticagrelor-treated subjects. The objective of this analysis was to evaluate the pharmacodynamic (PD) efficacy of P2Y12 antagonists in a contemporary real-world population. Materials and methodsThis PD study included 988 patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) and receiving dual therapy with aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor). Platelet function was assessed at day 1 and day 30 post-PCI by VerifyNow P2Y12 assay, multiple electrode aggregometry and vasodilator-stimulated phosphoprotein (VASP) assay. ResultsClopidogrel-treated patients (n = 324) had greater platelet reactivity than those receiving ticagrelor (n = 469) or prasugrel (n = 195) at both time points (p < 0.001 for all comparisons). No difference between ticagrelor and prasugrel was observed at day 1 with the VerifyNow P2Y12 assay (51.5 ± 2.8 vs. 42.7 ± 3.5 PRUs; p = 0.298), whereas ticagrelor achieved greater platelet inhibition at day 30 (48.1 ± 2.5 vs. 89.2 ± 4.2 PRUs; p < 0.001). Similar results were obtained with the VASP assay. Both prasugrel and ticagrelor had markedly lower HPR rates than clopidogrel and very high rates of LPR at both time points. ConclusionsPrasugrel and ticagrelor displayed more potent and consistent PD effects than clopidogrel in ACS patients undergoing PCI, with a trend towards greater platelet inhibition with ticagrelor during the maintenance phase of therapy compared to prasugrel.

Is there a Role for Oral Triple Therapy in Patients with Acute Coronary Syndromes Without Atrial Fibrillation?

Acute Coronary Syndrome (ACS) patients, despite treatment with Dual Anti- Platelet Therapy (DAPT), have up to 10% risk of recurrent Major Adverse Cardiac Events (MACE) in the short term. Here we review studies using more potent antithrombotic agent combinations to reduce this risk, namely Triple Therapy (TT) with the addition of an oral anticoagulant, PAR-1 antagonist, or cilostazol to DAPT (mainly aspirin and clopidogrel), and discuss the limitations of trials to date. Generally speaking, TT leads to an increase in bleeding. Vorapaxar showed a signal for reducing ischaemic events, but increased intracranial haemorrhage 3-fold in the subacute phase of ACS, although remains an option for secondary prevention beyond the immediate subacute phase, particularly if prasugrel or ticagrelor are not available. Non-Vitamin K Oral Anticoagulants (NOACs) all increased bleeding, with only modest reduction in MACE noted with low dose rivaroxaban. Rivaroxaban can be considered combined with aspirin and clopidogrel in ACS patients at high ischaemic and low bleeding risk, without prior stroke/TIA. The combination of P2Y12 inhibitor and NOAC, without aspirin, looks promising. DAPT may be replaced, not by TT, but by dual therapy comprising a NOAC with a P2Y12 inhibitor. More potent antithrombotic regimens increase bleeding and should only be considered on an individual basis, after careful risk stratification. Accurate risk stratification of ACS patients, for both ischaemic and bleeding risk, is essential to allow individualised treatment.

NFLUENCE OF CYP4F2*3 ON RESPONSE TO CLOPIDOGREL IN PATIENTS WITH ACUTE CORONARY SYNDROME

Background . Carriership of CYP4F2*3 (rs2108622, Val433Met) allelic variant can affect antiplatelet effect of clopidogrel, thus changing efficacy and safety of its standard dose. Aim. To study the impact of carriership of at least one CYP4F2*3 allele on the risk of resistance to clopidogrel in patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI). Material and methods . The study enrolled 81 patients with ACS and PCI: 64 males and 17 females, mean age 63.9±10.9 years. CYP4F2 allelic variants were detected by the method of real-time polymerase chain reaction. Platelet functional activity was evaluated by a portative aggregometer – the VerifyNow P2Y12 assay. Results . Pharmacogenetic testing showed that 40 (49.4%) of ACS patients had normal genotype ( CC ), 38 (46.9%) patients were carriers of one associated with reduced drug metabolism allele ( CT genotype), and 3 (3.7%) patients were homozygotes for T ( TT genotype). Genotype and allele distribution was in the Hardy-Weinberg equilibrium (c2=2.79; p=0.095). There were no statistically significant differences in CYP4F2*3 allele frequency between patients that are resistant to clopidogrel (PRU>208) and in patients with a normal response to clopidogrel (PRU<208): 36.8% vs 54.8% (р=0.17). Average platelet reactivity units (PRU) and average platelet inhibition (%) in patients with and without T allelic variant of CYP4F2 also were not significantly different: 165.34±51.03 PRU vs 174.8±51.06 PRU (p=0.407), respectively, and 29.51±21.59% vs 27.72±18.35%, respectively (p=0.69). Conclusion . Carriership of CYP4F2*3 allelic variant does not affect antiplatelet effect of clopidogrel in ACS patients. Further research on larger samples is needed to determine the role of CYP4F2 polymorphisms in personalization of clopidogrel antiplatelet therapy.

Genetic Polymorphism of CYP2C19 and Inhibitory Effects of Ticagrelor and Clopidogrel Towards Post-Percutaneous Coronary Intervention (PCI) Platelet Aggregation in Patients with Acute Coronary Syndromes.

BackgroundThe aim of this study was to observe the effects of genetic polymorphism of CYP2C19 on inhibitory effects of ticagrelor (Tic) and clopidogrel (Clo) towards post-percutaneous coronary intervention (PCI) platelet aggregation (IPA) and major cardiovascular events (MACE) in patients with acute coronary syndromes (ACS).Material/MethodsFrom August 2013 to March 2014, 166 patients with ACS undergoing PCI were selected. The patients were randomly grouped into the Tic group and the Clo group. IPA was detected by thromboelastography (TEG) at 1 week after taking the pills. Genotyping of CYP2C19 gene was determined by analysis of gene sequence detection. Patients were followed up for 1 month and MACE was observed.ResultsThe total IPA in the Clo group was significantly increased compared with the Tic group (P<0.05). The IPAs in the 3 subgroups of Clo group were all significantly increased compared with the 3 subgroups of the Tic group (all P<0.05). MACE was not significantly different between Clo and Tic groups (P>0.05). MACE had no significant difference among the 3 subgroups of the Tic group (P>0.05). MACE in the low metabolism subgroup of the Clo group was significantly increased compared with the fast metabolism subgroup and middle metabolism subgroup of Clo group (P<0.05). MACE was not significant different between the fast metabolism subgroup and the middle metabolism subgroup of the Clo group (P>0.05). MACE in the low metabolism subgroup of the Tic group was significantly decreased compared with the low metabolism subgroup of the Clo group (P<0.05).ConclusionsTicagrelor has a better effect on inhibition platelet aggregation than Clopidogrel in ACS patients undergoing PCI.

Assessment of P2Y12 inhibitor usage and switching in acute coronary syndrome patients undergoing percutaneous coronary revascularization

BackgroundDual antiplatelet therapy is recommended for patients with acute coronary syndrome (ACS) that undergo percutaneous coronary intervention (PCI). However, the effect of switching P2Y12 inhibitors between the loading dose and therapy after discharge is not well described. MethodsThis post-hoc analysis of a prospectively collected registry included 3219 consecutive ACS patients who underwent PCI. Patients were categorized into four groups: clopidogrel at load and discharge (C–C), loading dose of clopidogrel and discharged on prasugrel/ticagrelor (C–PT), loading dose of prasugrel/ticagrelor and discharged on clopidogrel (PT–C), and prasugrel/ticagrelor at load and discharge (PT–PT). ResultsWhile 77.6% of patients received the C–C treatment regimen and 13.6% received the PT–PT strategy, the strategy of P2Y12 switching was fairly common with 6.2% in the PT–C group and 2.6% in the C–PT group. While C–C was the most common treatment regimen, PT–C and PT–PT were more commonly used in STEMI patients than in NSTEMI or unstable angina patients. A significantly lower unadjusted incidence of the composite outcome (death, MI, and repeat revascularization) was appreciated in both the PT–C (1.0%) and PT–PT (2.3%) groups than the C–C group (4.0%). Propensity-score matched analysis still showed significantly reduced risk (HR=0.22, 95% CI 0.05–0.93, p=0.04) in the PT–C group vs. a matched group of C–C controls. ConclusionsThe strategy of utilizing a newer P2Y12 inhibitor and then switching to clopidogrel in ACS patients following PCI is used with some frequency in routine clinical practice and further studies should evaluate the safety and efficacy of such a strategy.

Safety and effectiveness of the new P2Y12r inhibitor agents vs clopidogrel in ACS patients according to the geographic area: East Asia vs Europe

BackgroundIn the setting of the Acute Coronary Syndrome (ACS), differences in response to prasugrel and ticagrelor between East Asian and European patients have not been investigated yet. MethodsThis is a sub-analysis of the “BleeMACS registry”. Patients admitted for ACS and underwent PCI from between 2012 and 2014 were stratified first according to their provenance, Europe vs. East Asia (China and Japan), and then by country. The adjusted rate of 1-year serious bleeding -safety end-point- and 1-year death/re-infarction -effectiveness endpoint- of the new P2Y12r inhibitors were compared. ResultsData of 10004 patients in Europe and 2332 patients in East Asia were collected. At baseline prior stroke (6% vs 9%, p<0.001, respectively) and type of ACS (59% vs 71% STEMI, 11% vs 21% Unstable Angina) were significantly different among the groups. At 1year follow-up no difference in bleeding (3% vs 3%, p=0.84) was found, while the between group incidence of death/re-infarction was significantly higher in the European centers (9% vs 5%, p<0.001). At the multivariate analysis, ticagrelor decreases the risk of MACE (Europe: HR 0.5, CI 0.3–0.9; East Asia: HR 0.5, CI 0.2–0.9), despite of a higher risk of bleeding in Caucasians (HR 1.7, CI 1.1–2.6). Prasugrel reduces death/re-infarction (HR 0.4, CI 0.2–0.6), without increasing bleeding (HR 0.9, CI 0.5–1.3). ConclusionsIn the setting of the ACS, the new anti-platelets drugs appear to be safe and efficacious at mid-term follow-up independently from the geographic area. Prasugrel seems to have the best risk–benefit, while ticagrelor appears safer in East Asians.

The diagnostic value and clinical relevance of thrombelastography and light transmission aggregometry based identification of low response to clopidogrel in ACS patients after percutaneous coronary intervention

Objective To obtain the incidence of low response (CLR) of acute coronary syndrome (ACS) patients after percutaneous coronary intervention(PCI) by Thrombelastography(TEG) and Light transmission aggregometry(LTA), and explore the correlation of CLR with clinical related factors and major adverse cardiac events. Methods This study is a cohort study.214 ACS patients in the Department of Cardiology of Peking University People′s Hospital, who were ready to treat with PCI between May 2014 and November 2014 were enrolled.Among them, 168 cases(78.5%) were male with an average age of (61.32±10.79) years; 46 cases(21.5%) were female with an average age of (68.72±8.38) years.The clinical data were recorded, such as history of present illness, the past medical history, clinical medication, and the results of coronary angiography.After taken clopidogrel 75 mg per day at least for 4 days, all patients were detected the contribution from ADP-stimulated platelets to maximal clot strength by TEG(TEG-ADP-Inhib), and detected ADP induced maximal platelet aggregation ratio by LTA(LTA-ADPMAX). The occurrence rate of CLR was calculated, and the correlation between results of the two assays were anylysed.Patients were divided into two groups according to CLR.Univariate analysis was used to compare the difference of clinical data between CLR group and non-CLR group, then Logistic regression analysis was conducted to find out the related risk factors that may influence the occurrence rate of CLR. Compare the correlation between CLR and MACE according to 6-month followed-up. Results There was negative correlations between LAT and TEG in the adenosine diphosphate induced platelet reactivity (r=-0.282, P=0.000). CLR was found in 115 (53.7%) patients by LTA and in 74(34.6% ) patients by TEG and the difference between the two CLR ratio was significant (χ2=10.486, P=0.001) .There were significant differences in age, smoking history and prior PCI/CABG history between CLR group and non-CLR group according to LTA grouping(t=2.829, P=0.005; χ2=11.058, P=0.001; χ2=4.252, P=0.039), and there was significant differences in history of cerebrovascular accident between CLR group and non-CLR group according to TEG grouping(χ2=4.584, P=0.032). Logistic regression analysis showed smoking history was the protective factor for CLR (OR=0.390, P=0.001), while history of cerebrovascular accident was the independent risk factor (OR=2.499, P=0.037) for CLR. According to 6-month followed-up, the incidence of clinical ischemic events and bleeding events in CLRLTA group was 5.2% and 0 respectively, in N-CLRLTA group was 10.1% and 3% respectively; the occurrence rate of clinical ischemic events and bleeding events was no significant difference between two groups(χ2=1.834, P=0.176; χ2=1.682, P=0.195). The incidence of clinical ischemic events and bleeding events in CLRTEG group was 8.1% and 0 respectively, in N-CLRTEG group was 7.1% and 2.1% respectively; the occurrence rate of clinical ischemic events and bleeding events was no significant difference between two groups(χ2=0.065, P=0.798; χ2=0.432, P=0.511). Conclusions The correlation between the testing results of TEG and LTA in ACS patients treated with clopidogrel was poor, CLR ratios detected by two assays were significantly different.Smoking history was the protective factor for CLR , while history of cerebrovascular accident was the independent risk factor for CLR.CLR was not the risk factor for MACE in ACS patients.(Chin J Lab Med, 2016, 39: 187-191) Key words: Thrombelastography; Densitometry; Ticlopidine; Acute coronary syndrome

Prasugrel (Efient®) with percutaneous coronary intervention for treating acute coronary syndromes (review of TA182): systematic review and economic analysis.

Acute coronary syndromes (ACSs) are life-threatening conditions associated with acute myocardial ischaemia. There are three main types of ACS: ST segment elevation myocardial infarction (STEMI), non-ST segment elevation myocardial infarction (NSTEMI) and unstable angina (UA). One treatment for ACS is percutaneous coronary intervention (PCI) plus adjunctive treatment with antiplatelet drugs. Dual therapy antiplatelet treatment [aspirin plus either prasugrel (Efient(®), Daiichi Sankyo Company Ltd UK/Eli Lilly and Company Ltd), clopidogrel or ticagrelor (Brilique(®), AstraZeneca)] is standard in UK clinical practice. Prasugrel is the focus of this review. The remit is to appraise the clinical effectiveness and cost-effectiveness of prasugrel within its licensed indication for the treatment of ACS with PCI and is a review of National Institute for Health and Care Excellence technology appraisal TA182. Four electronic databases (MEDLINE, EMBASE, The Cochrane Library, PubMed) were searched from database inception to June 2013 for randomised controlled trials (RCTs) and to August 2013 for economic evaluations comparing prasugrel with clopidogrel or ticagrelor in ACS patients undergoing PCI. Clinical outcomes included non-fatal and fatal cardiovascular (CV) events, adverse effects of treatment and health-related quality of life (HRQoL). Cost-effectiveness outcomes included incremental cost per life-year gained and incremental cost per quality-adjusted life-year (QALY) gained. An independent economic model assessed four mutually exclusive subgroups: ACS patients treated with PCI for STEMI and with and without diabetes mellitus and ACS patients treated with PCI for UA or NSTEMI and with and without diabetes mellitus. No new RCTs were identified beyond that reported in TA182. TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis in Myocardial Infarction 38) compared prasugrel with clopidogrel in ACS patients scheduled for PCI. No relevant economic evaluations were identified. Our analyses focused on a key subgroup of patients: those aged < 75 years who weighed > 60 kg (no previous stroke or transient ischaemic attack). For the primary composite end point (death from CV causes, non-fatal myocardial infarction or non-fatal stroke) statistically significantly fewer events occurred in the prasugrel arm (8.3%) than in the clopidogrel arm (11%). No statistically significant difference in major bleeding events was noted. However, there was a significant difference in favour of clopidogrel when major and minor bleeding events were combined (3.0 vs. 3.9%). No conclusions could be drawn regarding HRQoL. The results of sensitivity analyses confirmed that it is likely that, for all four ACS subgroups, within 5-10 years prasugrel is a cost-effective treatment option compared with clopidogrel at a willingness-to-pay threshold of £20,000 to £30,000 per QALY gained. At the full 40-year time horizon, all estimates are < £10,000 per QALY gained. Lack of data precluded a clinical comparison of prasugrel with ticagrelor; the comparative effectiveness of prasugrel compared with ticagrelor therefore remains unknown. The long-term modelling exercise is vulnerable to major assumptions about the continuation of early health outcome gains. A key strength of the review is that it demonstrates the cost-effectiveness of prasugrel compared with clopidogrel using the generic price of clopidogrel. Although the report demonstrates the cost-effectiveness of prasugrel compared with clopidogrel at a threshold of £20,000 to £30,000 per QALY gained, the long-term modelling is vulnerable to major assumptions regarding long-term gains. Lack of data precluded a clinical comparison of prasugrel with ticagrelor; the comparative effectiveness of prasugrel compared with ticagrelor therefore remains unknown. Well-audited data are needed from a long-term UK clinical registry on defined ACS patient groups treated with PCI who receive prasugrel, ticagrelor and clopidogrel. This study is registered as PROSPERO CRD42013005047. The National Institute for Health Research Health Technology Assessment programme.

Ticagrelor increases endothelial progenitor cell level compared to clopidogrel in acute coronary syndromes: A prospective randomized study

BackgroundThe clinical benefit of ticagrelor compared to clopidogrel in ACS patients suggested off-target property. Such pleiotropic effect could be mediated by circulating endothelial progenitor cells (EPC) which are critical for vascular healing. We aimed to investigate the impact of ticagrelor on EPC in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). MethodsWe prospectively randomized 106 ACS patients to ticagrelor or clopidogrel. Sub-populations of CD34+ circulating progenitor cells (PC) were analyzed by flow cytometry allowing one to determine the levels of CD34+ PC, CD34+CD45+ Hematopoietic PC, CD34+133+ immature PC and CD34+KDR+ EPC on admission and at 1month. Changes in PC level were calculated as the difference between 1month and baseline value. ResultsThe 2 groups were similar regarding baseline characteristics including PC numbers on admission. The 2 groups had similar change in overall CD34+ PC and hematopoietic CD34+45+ PC level (p=0.2). On the contrary, when considering CD34+133+ PC and CD34+KDR+ EPC, we observed that patients treated by ticagrelor had a significantly higher increase in levels of these PC subtypes compared to those treated by clopidogrel (0.23 (−0.33; 0.79) vs 0.00 (−0.5; 0.34); p=0.04 and 0.01 (−0.04; 0.05) vs −0.01 (−0.06; 0.03); p=0.02). Changes in the level of CD34+CD133+ PC correlated with platelet activity measured by the VASP index (r=−0.30; p=0.008). By contrast the increase in the level of CD34+KDR+ EPC in the ticagrelor group was independent of platelet activity. ConclusionsTicagrelor increases the number of EPC in ACS patients suggesting a benefit on endothelial regeneration that may participate in the pleiotropic property of the drug.